权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Identification and analysis of the genes responsible for inherited neurodegenerative disorders

鉴定和分析导致遗传性神经退行性疾病的基因

基本信息

批准号：
09470041
负责人：
KAKIZUKA Akira
金额：
$ 8.51万
依托单位：
Osaka Bioscience Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470041/
关键词：
neuronal cell death polyglutamine Machada-Joseph disease CAG Repeat PC12 SEK1 stress response Machado-Josephe病 ERDA1 MJD HD

项目摘要

A novel class of inherited human neurodegenerations is now known to be caused by expanded CAG repeats encoding polyglutamines. Polyglutamine-containing protein fragments have been shown to accumulate as aggregates in the nucleus and in the cytoplasm, and to induce cell death when expressed in cultured cells, leading to the proposal that polyglutamine aggregation is an important step in the pathogenesis. Supportingly, nuclear inclusions containing expanded polyglutamines have been identified in neurons from patient brains and in neurons from transgenic mouse models of this class of neural disorders.We analyzed the consequence of polyglutamine expression in PC12 neuronal cells. Activated SEK1 accumulated with nuclear but not cytoplasmic polyglutamine aggregations, which consequently triggers cell death. Cell death induced by polyglutamine expression was inhibited by a dominant-negative SEK1(DN-SEK1), but not by DN-SEKI tagged with a nuclear export signal. Steady state SEKI expression itself was enhanced by two to three fold. Nuclearly aggregated polyglutamines, which were identified in PML bodies, colocalized with not only activated SEKl but also activated c-Jun. We also observed that nuclear inclusion-positive neurons from Huntington disease brains expressed SEK 1.This study provides molecular links between neurodegeneration observed in polyglutamine diseases, cell death signalling kinase cascades, and nuclear subdomains related to cell death. We propose that the nuclear PML bodies containing polyglutamine aggregates activate the SEK1-JNK kinase cascade, resulting in transduction of a death signal.

现在已知一类新的遗传性人类神经变性是由编码多聚谷氨酰胺的CAG重复序列扩增引起的。含有多聚谷氨酰胺的蛋白质片段已显示在细胞核和细胞质中作为聚集体积累，并且当在培养的细胞中表达时诱导细胞死亡，从而提出多聚谷氨酰胺聚集是发病机制中的重要步骤。支持，核内含物含有扩大聚谷氨酰胺已被确定在神经元从病人的大脑和神经元从转基因小鼠模型的这类neural disorders.We分析的后果聚谷氨酰胺表达的PC 12神经元细胞。激活的SEK 1与细胞核而不是细胞质聚谷氨酰胺聚集体一起积累，从而触发细胞死亡。多聚谷氨酰胺表达诱导的细胞死亡被显性负性SEK 1（DN-SEK 1）抑制，但不被标记有核输出信号的DN-SEKI抑制。稳态SEKI表达本身增强了2至3倍。我们还观察到在亨廷顿病脑中的核包涵体阳性神经元表达SEK 1。这项研究提供了在多聚谷氨酰胺疾病中观察到的神经变性、细胞死亡信号激酶级联以及与细胞死亡相关的核亚结构域之间的分子联系。我们提出，核PML体含有聚谷氨酰胺聚集体激活SEK 1-JNK激酶级联，导致死亡信号的转导。